• 1989
• Litt et al.

  Discovery of SCN2A
• 2004
• Berkovic et al.

  SCN2A related benign familial epilepsy
• 2012
• Sanders et al.

  SCN2A as a cause for autism
• 2017
• Wolff et al.

  Correlations between functional outcome and phenotype
• 2018
• Sanders et al.

  Current knowledge on SCN2A-related disorders
• 2019
• Schwarz et al.

  SCN2A and episodic ataxia

SCN2A -related disorders are characterized by a wide clinical spectrum ranging from benign familial infantile seizures to developemental and epileptic encephalopathy. Furthermore, SCN2A is one of the most prominent monogenic causes of autism spectrum disorders. Variants causing both gain and loss of function have been identified as the underlying pathomechanism. Correlations between functional outcome and clinical phenotype includes: autism and/or late onset epilepsy for individuals with loss of function variants and neonatal onset self-limiting epilepsy or neonatal/infantile DEE with gain of function variant. As subset of individuals with self-limiting epilepsy develop episodic ataxia later in childhood.

• 2008
• Holland et al.

  First association of SCN3A and epilepsy
• 2020
• Zamam et al.

  Delineation of the phenotype

SCN3A -related disorders are characterized mainly by epilepsy often associated with brain malformations such as polymicrogyria (abnormal gyration of the brain). Affected individuals often have intellectual disability. Seizure types varies, and includes focal, febrile, myoclonic and tonic seizures among others. Functional studies have revealed both gain and loss of function as underlying pathomechanism. Because of a small number of known affected individuals, correlations between functional outcome, genotype and phenotype are still sparse. The limited data there is, suggests that brain malformations are mainly seen in individuals with gain of function variants, while epilepsy and intellectual disability are seen in both individuals with gain and loss of function variants.

• 1995
• Burgess et al.

  Discovery of SCN8A
• 2012
• Veeramah et al.

  First epilepsy patient described
• 2014
• Ohba et al.

  Further characterization of the phenotype
• 2015
• Wagnon et al.

  First SCN8A DEE mouse model
• 2015
• Larsen et al.

  Delineation of the phenotype
• 2016
• Boerma et al.

  Sodium channel blocker treatment for SCN8A DEE
• 2016
• Gardella et al.

  Description of SCN8A in BFIE
• 2017
• Wagnon et al.

  First description of individuals with LOF missense variants
• 2017
• Lopez-Santiago et al.

  Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy
• 2018
• Gardella et al.

  The phenotype of SCN8A DEE
• 2019
• Bunton-Stasyshyn et al.

  Prominent role of forebrain excitatory neurons in SCN8A encephalopathy
• 2020
• Lenk et al.

  Antisense oligonucleotide treatment in SCN8A mouse model
• 2021
• Johannesen et al.

  Correlation between functional outcome and phenotype

SCN8A, encoding the alpha subunit of the voltage-gated sodium channel Nav1.6, is associated with a wide clinical spectrum of epilepsies ranging from benign familial infantile seizures (BFIS), over an intermediate phenotype with treatable seizures and mild-moderate intellectual disability, to severe developmental and epileptic encephalopathies (DEEs). SCN8A-DEE is characterized by early onset intractable seizures, cognitive impairment, movement disorders, cortical visual impairment and severe gastrointestinal symptoms. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms, evolving to clonic or bilateral tonic-clonic manifestations. Spasm-like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. In contrast, individuals with BFIS have well controlled self-limiting epilepsy with no other neurological deficits and normal cognition. In addition, rare clinical presentations with ID, autism spectrum disorder and movement disorders without epilepsy have been described.